Copper deficiency is an independent risk factor for mortality in patients with advanced liver disease

Background and Aim: Copper is an essential trace metal serving as a cofactor in innate immunity, metabolism, and iron transport. We hypothesize that copper deficiency may influence survival in patients with cirrhosis through these pathways. Methods: We performed a retrospective cohort study involving 183 consecutive patients with cirrhosis or portal hypertension. Copper from blood and liver tissues was measured using inductively coupled plasma mass spectrometry. Polar metabolites were measured using nuclear magnetic resonance spectroscopy. Copper deficiency was defined by serum or plasma copper below 80 mu g/dL for women or 70 mu g/dL for men. Results: The prevalence of copper deficiency was 17% (N = 31). Copper deficiency was associated with younger age, race, zinc and selenium deficiency, and higher infection rates (42% vs. 20%, p = 0.01). Serum copper correlated positively with albumin, ceruloplasmin, hepatic copper, and negatively with IL-1 beta. Levels of polar metabolites involved in amino acids catabolism, mitochondrial transport of fatty acids, and gut microbial metabolism differed significantly according to copper deficiency status. During a median follow-up of 396 days, mortality was 22.6% in patients with copper deficiency compared with 10.5% in patients without. Liver transplantation rates were similar (32% vs. 30%). Cause-specific competing risk analysis showed that copper deficiency was associated with a significantly higher risk of death before transplantation after adjusting for age, sex, MELD-Na, and Karnofsky score (HR: 3.40, 95% CI, 1.18-9.82, p = 0.023). Conclusions: In advanced cirrhosis, copper deficiency is relatively common and is associated with an increased infection risk, a distinctive metabolic profile, and an increased risk of death before transplantation.